Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytoplasmic beta-catenin protein is implicated in signal transduction and associates with both the cell-cell adhesion protein E-cadherin and the tumor suppressor gene product APC. We determined the primary structure of the human beta-catenin gene (CTNNB1) by analysis of cDNA and genomic clones. The size of the complete gene was determined to be 23.2 kb. Restriction mapping and partial sequence analysis revealed 16 exons. All splice donor and acceptor sites were conformable to the GT/AG rule. The exon size ranged from 61 to 790 bp. Half of the introns were smaller than 550 bp, with the smallest being 84 bp and the longest being 6700 bp. The intron-exon boundaries did not coincide either with conserved sites in the 12 armadillo repeat sequences of beta-catenin or with intron-exon boundaries in the armadillo gene of Drosophila. A major site for transcription initiation was identified as an A residue 214 nucleotides upstream of the ATG initiation codon. The resulting transcript is 3362 nucleotides long. Compared to the previously published mRNA sequence, additional residues were identified, 16 at the 5' end and 766 at the 3' end of the mRNA. An alternative splice acceptor site within exon 16 reduced the 3' UTR sequence by 159 bp. Polymerase chain reaction on cDNA from 14 human cell lines demonstrated the general occurrence of both splice variants. The 5'-flanking region is highly GC-rich and lacks a CCAAT box, but contains a TATA box and potential binding sites for several transcription factors, such as NF kappa B, SP1, AP2, and EGR1. Both a 437-bp fragment and a 6-kb fragment, containing about 4.7 kb of the 5'-flanking region in addition to the noncoding exon 1 and 1 kb of intron 1, showed clear promoter activity when these fragments were linked to a secreted alkaline phosphatase reporter gene and transfected into a mouse epithelial cell line.
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PMID:Genomic organization of the human beta-catenin gene (CTNNB1). 883 5

Exon trapping was performed from a partial cosmid, PAC, and P1 clone contig from human chromosome 21 between MX1 and 21qter to identify genes that may be involved in the pathogenesis of Down syndrome or several of the genetic diseases that map to chromosome 21q22.3. One 19-bp exon showed identity to three ESTs. The complete sequence of the EST clones, RT-PCR, and cDNA library screening were used to determine the full-length cDNA sequence of 2.2 kb with an open reading frame of 256-amino-acids. The putative 256-amino-acid peptide has homology with a hypothetical Caehorhabditis elegans protein of unknown function. Northern blot analysis of this gene, termed C21orf2 (chromosome 21 open reading frame 2), revealed two ubiquitously expressed mRNAs of 2.2 and 1.2 kb produced by use of alternative polyadenylation sites. Hybridization of the EST clones to a cosmid contig in chromosome 21q22.3 mapped C21orf2 just distal to PFKL, a critical mapping region for several genetic diseases. Comparison to publicly available genomic sequence, and additional data, revealed that the gene is split into seven exons over 10.5 kb, further refining the mapping position to only 1.2 kb distal to PFKL with the direction of transcription toward the centromere. The 5'UTR is contiguous with D21S400, and intron 2 contains a 52-bp VNTR polymorphism. Given its mapping position, C21orf2 is a candidate for involvement in disorders including autoimmune polyglandular disease type I (also called autoimmune polyendocrinopathy candidiasis ectodermal dystrophy or APECED) and the autosomal nonsyndromic deafness loci, DFNB8 and DFNB10. Mutation analysis using sequencing of RT-PCR and genomic DNA-derived PCR products, SSCP, and Southern and Northern blot analyses in APECED patients excluded C21orf2 as the gene for APECED.
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PMID:Characterization of a novel gene, C21orf2, on human chromosome 21q22.3 and its exclusion as the APECED gene by mutation analysis. 946 97

Abnormalities of chromosome 1q21 are common in B-cell malignancies and have been associated with a poor response to therapy. The nature of the involved gene(s) on chromosome 1q21 remains unknown. A cell line (CEMO-1) has recently been established from a patient with precursor-B-cell acute lymphoblastic leukemia (ALL), which exhibited a t(1;14)(q21;q32). To identify the gene involved in this translocation, we have cloned both rearranged IGHJ alleles using long-distance inverse polymerase chain reaction (LDI-PCR). Two IGHJ fragments were amplified from CEMO-1 DNA and sequenced. One allele showed novel sequences upstream of JH5 with no homology to either IGH or any other sequences on the databases. Using a single-copy Xho I fragment immediately 5' of JH5, PAC clones were isolated and mapped to chromosome 1q21 on normal metaphases by fluorescence in situ hybridization (FISH), confirming that this allele represented the t(1;14)(q21;q32) breakpoint. Sequence analysis of the 1q21 Xho I fragment showed identity with an expressed sequence tag (EST), and this probe was therefore used to probe Northern blots. Two transcripts of 6.3 kb and 4.2 kb expressed at low level in mRNA from all tissues were detected: a third transcript of 1.6 kb was expressed only in thymus, spleen, and small intestine. Full-length BCL9 cDNA clones were obtained from a normal human fetal brain cDNA library supplemented by 5' and 3' RACE. Sequence analysis predicted a protein of 1394 amino acids containing 18% proline, 11% glycine, 11% serine, and 6% methionine, but no recognizable protein motifs or significant homologies to any other known proteins. The CEMO-1 1q21 breakpoint fell within the 3' UTR of the BCL9 gene. Low-level expression of BCL9 was detected in Epstein-Barr virus-transformed normal B cells by Northern blot; in contrast, abundant BCL9 expression was observed in CEMO-1, indicating that deregulated expression of this gene was one pathological consequence of the translocation. Screening of a panel of 39 B-cell malignancies with 1q abnormalities by Southern blot showed one additional case with a breakpoint in the 3' UTR of BCL9, indicating that this was a recurrent breakpoint. FISH analysis using an 850-kb YAC spanning BCL9 identified a further case with t(1;22)(q21;q11) causing juxtaposition of BCL9 to the IGlambda locus. Other breakpoints were heterogeneous, falling both centromeric (10 cases) and telomeric (10 cases) of the BCL9 gene. These data suggest that BCL9 may be the target of translocation in some B-cell malignancies with abnormalities of 1q21 and that deregulated BCL9 expression may be important in their pathogenesis.
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PMID:Molecular cloning of translocation t(1;14)(q21;q32) defines a novel gene (BCL9) at chromosome 1q21. 949 Jun 69

The beclin 1 (BECN1) gene encodes a 60-kDa coiled-coil protein that interacts with the prototypic apoptosis inhibitor Bcl-2. Previous studies indicate that beclin 1 maps to a region approximately 150 kb centromeric to BRCA1 on chromosome 17q21 that is commonly deleted in breast, ovarian, and prostate cancer. The complete cDNA sequence of beclin 1 encodes a 2098-bp transcript, with a 120-bp 5' UTR, 1353-bp coding region, and 625-bp 3' UTR. Hybridization screening of a human genomic PAC library identified PAC 452O8, which contains the complete beclin 1 gene. Determination of the exon-intron structure of beclin 1 reveals 12 exons, ranging from 61 to 794 bp, which extend over 12 kb of the human genome. FISH analysis of human breast carcinoma cell lines using PAC 452O8 as probe identified allelic beclin 1 deletions in 9 of 22 cell lines. Sequencing of genomic DNA from 10 of these cell lines revealed no mutations in coding regions or splice junctions. Additionally, Northern blot analysis of 11 cell lines did not identify any abnormalities in beclin 1 transcripts. These results indicate that human breast carcinoma cell lines frequently contain allelic deletions of beclin 1, but not beclin 1 coding mutations.
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PMID:Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. 1039

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine involved in early conceptus development in pig. We isolated a PAC clone containing the porcine LIF gene and determined the complete DNA sequence of the gene, which spans about 6.3 kb and consists of five exons including three alternative first exons (1D, 1M, 1T) spliced onto common second and third exons. The LIF-D transcript encodes a protein of 202 amino acids sharing 87, 84, and 78% identity with respectively human, ovine, and murine leukemia inhibitory factors. The LIF-M and LIF-T transcripts both encode a truncated protein of 158 amino acids. Two SNP markers within untranslated regions of the LIF cDNA were identified. One SNP is located in the 5'-UTR of the alternative exon 1T while the other SNP is located in the 3'-UTR of exon 3. Based on fluorescence in situ hybridization and radiation hybrid mapping, the porcine LIF gene was assigned to chromosome 14q2.1-->q2.2.
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PMID:Molecular characterization and chromosome assignment of the porcine gene for leukemia inhibitory factor LIF. 1147 86

WNT signals are transduced to beta-catenin - TCF pathway, JNK pathway, or Ca2+-releasing pathway through WNT receptors. FRAT1, FRAT2, and PAR-1 are positive regulators of WNT - beta-catenin pathway. APC, AXIN, NKD1, NKD2, and Strabismus (STB1, STB2) are negative regulators of WNT - beta-catenin pathway. Here, biological significance of WNT3-WNT14B/WNT15 gene cluster (human chromosome 17q21) and WNT3A-WNT14 gene cluster (human chromosome 1q42) will be reviewed. Total-amino-acid identity between WNT3 and WNT3A is 84.2%, and that between WNT14 and WNT14B is 61.4%. WNT3A and WNT14B show reciprocal regulation by all-trans retinoic acid in NT2 cells and by beta-estradiol in MCF-7 cells. Exon-intron structures are well conserved between WNT3-WNT14B gene cluster and WNT3A-WNT14 gene cluster, except for the existence of an additional intron in 3'-UTR of WNT3. Capicua pseudogene and AK024248-related sequence are located within intergenic region of human WNT3A-WNT14 gene cluster, but not within intergenic regions of human WNT3-WNT14B gene cluster and mouse Wnt3a-Wnt14 gene cluster. Integration of mouse mammary tumor virus (MMTV) into mouse Wnt3-Wnt14b gene cluster leads to carcinogenesis. Because these WNT gene clusters might be fragile sites in the human genome, implication of WNT3 or WNT3A in cancer as well as implication of WNT14 or WNT14B in connective tissue disease and congenital joint malformation should be elucidated in the future. WNT3, WNT3A, WNT14, and WNT14B might be applicable to tissue engineering of neuron and joint in the field of regenerative medicine, and as an early diagnostic marker in the field of clinical oncology.
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PMID:WNT3-WNT14B and WNT3A-WNT14 gene clusters (Review). 1201 73

Many families experience an apparently inherited increased risk of colorectal cancer (CRC) similar to the known syndromes familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). Besides these high-risk syndromes, approximately 10% of all CRC cases come from families with 2 affected 1st-degree relatives, and even 1st-degree relatives to a single case of CRC are at increased risk. Risk subjects from these families frequently show polyps at colonoscopy, which suggests the APC gene as a good candidate susceptibility gene for these attenuated polypotic syndromes. We used the sensitive DHPLC technique to search for possible predisposing germline mutations in the entire APC gene in 91 risk subjects from these high- and low-risk syndromes with unknown predisposing genes. Most exons were also screened for mutations in 96 normal controls and 96 colorectal cancer cases. In our study we probably have identified the most common APC variants in a Swedish population. Among 30 germline variants identified, 1 clearly pathogenic nonsense mutation and 11 putative pathogenic variants (10 missense and one 3' UTR) were found in 20 index patients (22%). Twelve silent as well as 5 intronic variants were considered nonpathogenic. Two of the missense variants found here, E1317Q and D1822V, have previously been related to a difference in risk of colorectal cancer. One variant, 8636C>A, located within the 3' UTR region of the APC gene, was suggested to constitute an additional low risk allele with a similar relative risk as the Jewish I1307K mutation (OR = 1.8; 95% CI, 0.96-3.40). The question of whether all the other variants confer an increased colorectal cancer risk warrants future large association studies.
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PMID:Definition of candidate low risk APC alleles in a Swedish population. 1512 87

Fission yeast Ste9/Srw1 is a family member of the Fizzy-related APC activators that promote the ubiquitination and degradation of mitotic cyclins and other substrates at the end of mitosis and G1. These proteins are highly regulated during the cell cycle at the level of gene transcription and protein phosphorylation in order to guarantee the correct order of events during the cell cycle. Here we propose mRNA decay as a novel mechanism that regulates ste9+ gene expression during the cell cycle. We have characterized the elements in the 3'UTR of the ste9 mRNA responsible for this mechanism. Moreover, we demonstrate that the instability of ste9 mRNA is important for downregulating Ste9 levels in G2, allowing appropriate cyclin B accumulation to promote timely entry into mitosis.
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PMID:The fission yeast APC activator Ste9 is regulated by mRNA decay. 1662 99

To isolate the CYP1A1 promoter/enhancer from zebrafish, a PAC genomic library was screened with sequence derived from the 5'UTR of the zfCYP1A1 cDNA. Sequence was identified that contained CAAT and TATA boxes, had a large intron within the 5'UTR, and showed 100% sequence identity to zfCYP1A1 cDNAs in the 5'UTR and initial 300 bp of the open reading frame. Oligonucleotides complementary to the 5'UTR were used to detect zfCYP1A1 mRNA in zebrafish liver cells (ZFL) exposed to TCDD, thus identifying the gene as a TCDD-inducible CYP1A1. Sequence analysis revealed that the 5' flanking region contained eight putative xenobiotic response elements (XRE) arranged in two distinct clusters. One cluster was localized between -580 and -187 and contained three XREs and two XREs bound zfAHR2 . rtARNTb complexes in vitro. However, this region was incapable of conferring TCDD-responsiveness to an SV40 promoter. In contrast, the region between -2608 and -2100 contained five XREs and was capable of driving TCDD-inducible expression when placed in either a forward or reverse orientation upstream or downstream of an SV40 promoter. Thus, the zfCYP1A1 gene has similar structural features to mammalian CYP1A1s and will be ideal for the analysis of AHR-mediated gene regulation in an aquatic organism.
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PMID:Isolation and characterization of a dioxin-inducible CYP1A1 promoter/enhancer region from zebrafish (Danio rerio). 1824 94

It was previously demonstrated that miR-199a was downregulated in testicular germ cell tumor (TGCT), probably due to hypermethylation of its promoter. Further study found that re-expression of miR-199a in testicular cancer cells (NT2) led to suppression of cell growth, cancer migration, invasion and metastasis. More detailed analyses showed that these properties of miR-199a could be assigned to miR-199a-5p, one of its two derivatives. The biological role of the other derivative, miR-199a-3p in TGCT, remains largely uncharacterized. In this report, we identified DNA (cytosine-5)-methyltransferase 3A (DNMT3A), the de novo methyltransferase, as a direct target of miR-199a-3p using a 3'-UTR reporter assay. Transient expression of miR-199a-3p in NT2 cells led to decrease, while knocking down of miR-199a-3p in a normal human testicular cell line (HT) led to elevation, of DNMT3A2 (DNMT3A gene isoform 2) mRNA and protein levels. In clinical samples, DNMT3A2 was significantly overexpressed in malignant testicular tumor, and the expression of DNMT3A2 was inversely correlated with the expression of miR-199a-3p. However, DNMT3A did not affect miR-199a expression in NT2 cells. Further characterization of miR-199a-3p revealed that it negatively regulated DNA methylation, partly through targeting DNMT3A. Overexpression of miR-199a-3p restored the expression of APC and MGMT tumor-suppressor genes in NT2 cells by affecting DNA methylation of their promoter regions. Our studies demonstrated the deregulation of miR-199a-3p expression in TGCT may provide novel mechanistic insights into TGCT carcinogenesis and suggested a potentially therapeutic use of synthetic miR-199a-3p oligonucleotides as effective hypomethylating compounds in the treatment of TGCT.
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PMID:microRNA-199a-3p, DNMT3A, and aberrant DNA methylation in testicular cancer. 2395 88


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